Combat operations in Afghanistan and Iraq have been associated with increased prevalence of both traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) among veterans. Recent data demonstrate that those with TBI-related injuries concurrent with PTSD, experience worsening of symptoms in the delayed post- deployment period. The compounded effects of PTSD-TBI make the diagnosis, management, treatment, and rehabilitation of those affected a challenge in VA, military, and civilian medical facilities. It has become increasingly important to recognize symptoms in veterans with comorbid PTSD-TBI compared to those symptoms associated with TBI or PTSD alone, in the rehabilitation period. One mechanism to have recently come into focus to explain the compounded effects of comorbid PTSD-TBI is impaired cortical activation, a condition that has been observed following either TBI or PTSD alone. TBI itself results in hypoactivity of cortical neurons, which is mirrored in patients affected with onl PTSD. Surprisingly, to date, there have been few preclinical studies to evaluate the impact of combined TBI and PTSD on neuronal activity in the prefrontal cortex, adding to the significance and conceptual innovation of the proposed project. This knowledge gap will be addressed in the current application by examining cortical hypoactivation in comorbid PTSD-TBI, using mouse models of mild, non-contusive TBI and PTSD. Cortical hypoactivation will be evaluated at numerous levels, including markers of excitatory neurotransmission, dendritic structure, cortical volume, neuronal activation and cortically-mediated behaviors. The strength of this application is the comprehensive analysis of cortical function from receptor expression and activation to behavioral measures and use of novel imaging modalities to examine the longitudinal progression of symptoms. In addition, rehabilitative interventions using novel glutamatergic compounds, such as memantine, will be employed as translationally-relevant therapies for comorbid PTSD-TBI. We hypothesize that the combination of PTSD-TBI will exacerbate behavioral and molecular endpoints, functional/structural assessments of excitatory neurotransmitter levels, dendritic morphology, cortical volume, neuronal plasticity and cortical activation compared to either condition alone and that these deficits will be reversed by neurotherapeutic intervention. We will test this hypothesis using the following Specific Aims: 1.) Evaluate the influence of comorbid PTSD- TBI on cognitive behaviors, neuronal structure and markers of excitatory neurotransmission compared to either condition alone, 2.) Quantify the long-term impacts of comorbid PTSD-TBI on cortical neurotransmitter levels (neurochemical), volume (structural) and neuroactivation (functional) using novel magnetic resonance (MR) imaging techniques in a longitudinal manner in vivo compared to either condition alone, 3.) Evaluate the ability of neurotherapeutic treatment to improve/restore structural and neurotransmitter-related deficits associated with PTSD-TBI and thereby, to improve cognitive behaviors and cortical function.